Solid phase nitrile synthesis

ABSTRACT

A nitrile compound is prepared by treating a solid supported amide to dehydrate it and cleave it from the support in one operation. The preparation involves acetylation of the amide compound in the presence of a base at a temperature of less than 100° C.

This invention relates to solid phase nitrile synthesis andparticularly, although not exclusively, provides a method of preparing anitrile compound.

An object of the present invention is to provide an advantageous methodof preparing a nitrile compound.

According to the invention, there is provided a method of preparing anitrile compound, the method comprising treating a solid supported amideto cause formation of the nitrile compound and cleavage from thesupport.

Thus, there is suitably provided a solid phase reaction which allowsformation of nitrites with concomitant release of the solid support.Preferably, in the method, the amide is dehydrated. Preferably the amideis treated such that cleavage and dehydration of the amide areaccomplished in one operation.

Said nitrile compound is preferably of formula RCN where R represents anoptionally-substituted alicyclic, aliphatic or aromatic (which includesheteroaromatic) group.

Except where otherwise stated in this specification, an alicyclic groupmay have five or six carbon atoms; it preferably has six. Such a groupmay be optionally-substituted by any atoms or groups hereinafterdescribed. Additionally, a said alicyclic group may be optionallysubstituted by forming a polycyclic, for example bicyclic, ring systemwith other cyclic or aromatic groups. In one embodiment, an alicyclicgroup may form a bicyclic ring system with a five or six-member aromaticgroup, an example of this arrangement being a tetrahydronaphthyl group.

Except where otherwise stated in this specification, optionalsubstituents of alicyclic, aliphatic and aromatic groups include halogenatoms for example fluorine, chlorine or bromine atoms andoptionally-substituted phenyl, nitro, cyano, alkoxy, hydroxy, amino,alkylamino, sulphinyl, alkylsulphinyl, sulphonyl, amido, alkylamido,alkoxycarbonyl, haloalkyoxycarbonyl and haloalkyl groups. optionalsubstituents, especially nucleophilic groups, also include protectedforms of any of the aforesaid.

Except where otherwise stated in this specification, an aliphatic groupsuitably has up to 8, preferably up to 6, more preferably up to 4,especially up to 2, carbon atoms and may be of straight chain or, wherepossible, branched chain structure.

Except where other stated in this specification, an aromatic group mayinclude a monocyclic or polycyclic (fused) aromatic ring system. Anyaromatic ring of such a system may include one or more heteroatomsselected from nitrogen, oxygen and sulphur atoms. Preferred monocyclicor polycyclic groups include five or six ring atoms.

Where R represents an alicyclic group, it is preferably anoptionally-substituted group which includes six ring atoms. Preferablysaid alicyclic group is substituted so as to define a polycyclic group,especially a bicyclic group, suitably wherein one ring thereof isaromatic. An especially preferred alicyclic group is anoptionally-substituted, preferably unsubstituted, tetrahydronaphthylgroup.

Where R represents an aliphatic group, such a group is preferablysubstituted. It may be substituted, preferably monosubstituted, suitablyby an amino, or a derivative of an amino (especially a protected) groupor an optionally-substituted aromatic group. Examples of protected aminogroups include Fmoc- and Boc-protecting groups. A preferred aliphaticgroup R is of formula

wherein X is a substituent, especially a protected amino group and R¹ isan optionally substituted alkyl (preferably a C₁₋₈, more preferably C₁₋₄alkyl, especially a methyl) group.

Examples of aliphatic groups optionally-substituted by an aromatic groupinclude a C₁₋₈, preferably a C₁₋₆, more preferably a C₁₋₄, especially aC₁₋₂, alkyl group substituted by an optionally-substituted, especiallyan unsubstituted, phenyl group. A preferred such group is aphenylethylyl group.

Where R represents an aromatic group, it preferably represents anoptionally-substituted phenyl or optionally-substituted bicyclic (fused)group. A preferred optionally-substituted phenyl group is substituted byany of the substituents described above, the preferred ones of whichinclude an optionally-substituted phenyl group or a nitro, alkoxy(suitably a C₁₋₈, preferably C₁₋₆, more preferably C₁₋₄, especially aC₁, alkoxy) group. A preferred bicyclic (fused) group comprises a benzomoiety fused to a five-membered heteroaromatic moiety and preferablyrepresents a benzoheterophenyl (e.g. benzothiophenyl) group.

Preferably, group R incorporates an aromatic moiety and/or an aminogroup, especially a protected amino group. More preferably, group Rincorporates an aromatic moiety.

Said amide may be of formula

RCONR²-SS  II

wherein R² is a hydrogen atom or an optionally-substituted alkyl groupand SS represents a solid support.

R² is preferably a hydrogen atom.

SS preferably includes a moiety of formula

wherein the free bond is bonded to the nitrogen atom in the amide offormula II and wherein R³, R⁴ and R⁵, independently represent a hydrogenatom or an optionally-substituted alkyl or aromatic group, provided thatat least one of groups R³, R⁴, or R⁵ represents anoptionally-substituted aromatic group. Atoms or groups on one of R³ R⁴or R⁵ may be bonded to another one of R³ R⁴ or R⁵ so that bridging atomsor groups are defined between a part of one of R³, R⁴ or R⁵ and a partof another of R³, R⁴ or R⁵

Preferably, R⁵ represents a hydrogen atom or an optionally-substituted,especially an unsubstituted, alkyl group. More preferably, R⁵ representsa hydrogen atom.

Preferably, R³ does not represent a hydrogen atom. Preferably, R³represents an electron-donating group. R³ preferably represents anoptionally-substituted aromatic group. R³ may be optionally-substitutedby one or more electron donating groups, for example by alkoxy,preferably C₁₋₄, more preferably C₁₋₂, especially methoxy, groups.Preferably, R³ represents an optionally-substituted phenyl group. R³ maybe optionally-substituted by a bridging atom or group which defines abridge between groups R³ and R⁴

Wherein R³ is substituted, it is preferably substituted in the ortho-and/or para-position(s).

Preferably, R⁴ does not represent a hydrogen atom. Preferably, R⁴represents an electron-donating group. R⁴ preferably represents anoptionally-substituted aromatic group. R⁴ may be substituted by one ormore electron-donating groups, for example by a group incorporating an—O— moiety. Preferably R⁴, represents an optionally-substituted phenylgroup. Where a bridge is defined between groups R³ and R⁴ said bridgemay be defined by —O— or —S— moieties, especially by an —O— moiety whichsuitably forms with part of groups R³ and R⁴ a component of asix-membered ring. Where R⁴ is substituted, it is preferably substitutedin the ortho and/or para position(s).

Preferably, one of R³ and R⁴, more preferably R⁴, is linked to a polymersupport.

In one embodiment, SS may represent

wherein PS represents a polymer-support and the free bond between thephenyl groups represents the point of attachment to the nitrogen atom informula II.

In another embodiment, SS may represent

where the free bond is as described above.

Preferably the method comprises treating said solid supported amide tocause formation of the nitrile compound and cleavage of it from thesupport.

Preferably, in the method, formation of the nitrile compound andcleavage of it from the support occur substantially concurrently.

Preferably, preparation of said nitrile compound involves dehydratingsaid solid supported amide. In the preparation of the nitrile compound,the amide may be acetylated, suitably by trifluoroacetylation, whichsuitably allows cleavage/dehydration in one operation. Dehydration maybe undertaken in the presence of a base. Preferred dehydrating agentsare highly electrophilic and may include: a nitrogen-containing base,for example an aromatic nitrogen containing base such as pyridine; anacid halide, especially an acid chloride and preferably one including anelectron withdrawing group attached to the carbonyl carbon thereof,wherein suitably a haloalkyl, preferably a chloroalkyl, especially amulti-chloro alkyl, such as trichloromethyl, may be used; and Burgessreagent ((methoxycarbonylsulphamoyl)triethylammonium hydroxide innersalt).

The treatment of said solid supported amide is preferably carried out inan aprotic suitably an organic solvent. The reaction is suitably carriedout at a temperature of less than 100° C., preferably less than 50° C.,more preferably at less than 30° C., especially at ambient temperature.

After the treatment, the mixture produced may be filtered to separatethe nitrile compound from the solid support and then isolated bystandard techniques. Said solid supported amide may be prepared bytreatment of an amine with a carboxylic acid or a carboxylic acidderivative. Where the nitrile compound is of formula RCN, said amine maybe treated with a compound of formula

RCOY  VI

wherein Y represents an hydroxy group, a carboxylic acid residue, forexample a halogen atom or any electron withdrawing leaving group such asthose derived from HOBt, HOAt, N-hydroxysuccinimide, 2- or4-nitrophenol, pentafluorophenol, cyanomethyl and N,N′-dialkyl-O-acylureas.

The amine used to prepare the amide may be of general formula

wherein R³, R⁴ and R⁵ are as described above.

Preferably, the amide is prepared from the amine by contacting the amineof formula VII with said compound of formula VI, suitably in thepresence of a base and suitably in an aprotic organic solvent. Thereaction is preferably carried out at a temperature of less than 100°C., preferably less than 50° C., more preferably less than 30° C.,especially at ambient temperature.

The invention extends to any novel nitrile compound described herein.

The invention further extends to any novel intermediate describedherein.

Specific embodiments of the invention will now be described, by way ofexample.

Aromatic and aliphatic nitrites have been prepared through dehydrationof secondary amides derived from carboxylic acids or carboxylic acidderivatives and resin bound electron rich aromatic methylamines. Schemes1 and 2 below summarize the preparation starting from Sieber and Rinkresins respectively, wherein R is an optionally-substituted aromatic oraliphatic group.

Referring to schemes 1 and 2, the Sieber and Rink resins are examples ofelectron rich methylamines which are reacted with carboxylic acids oracid chlorides to prepare secondary amides which can then be dehydrated,for example using excess trifluoracetic anhydride and pyridine in drydichloromethane overnight to furnish the nitrile derivative (RCN)directly in solution.

Specific reactions undertaken are now described. Examples 1 to 10describe the preparation of amides; and examples 11 to 24 describe thepreparation of nitrile compounds from corresponding amides. In Examples11 to 18, 23 and 24 dehydration/cleavage to the nitrites is achievedusing TFAA-pyr in DCM; in examples 19 and 20, dehydration/cleavage iseffected by the use of Burgess reagent; and in Examples 21 and 22dehydration/cleavage is effected by use of trichloracetyl chloride.

The following abbreviations are used herein:

TBTU—2-(1H-benzotriazolyl)-1,1,3,3-tetramethyluronium tetrafluoroborate

HOBt—1-hydroxybenzotriazole

DIEA—N,N-diisopropylethylamine

TFAA—trifluoroacetic anhydride

DCM—dichloromethane

DMF—dimethyl formamide

Fmoc—fluorenylmethoxycarbonyl

Boc—butoxycarbonyl

Resins described herein were purchased from Nova Biochem. Sieber andRink resins were purchased in Fmoc protected forms. Deprotection, wherenecessary, is generally undertaken as follows: Resin (1 g) was suspendedin DMF (20 ml) and piperidine (5 ml) was added. The mixture was stirredat room temperature for 30 minutes, then washed with DMF, MeOH, DCM,MeOH, DCM, MeOH and dried in vacuo.

Burgess reagent described herein may be prepared as described in G. M.Atkins, Jr and E. M. Burgess, J. Amer. Chem. Soc., 1968, 90, 4744.

EXAMPLE 1 3-Phenylpropionyl-Sieber Resin

To a suspension of Fmoc-deprotected Sieber resin (0.62 mmol/g, 150 mg)in dry DCM was added N, N-diisopropylethylamine (65 μl) followed by3-phenylpropionyl chloride (55 μl) and the suspension stirred at ambienttemperature for 2 hours. The resin was then washed (using DCM, methanol,DCM, methanol), then dried under vacuum.

EXAMPLE 2 Amide Derived From 2-Biphenyl Carboxylic Acid and Sieber Resin

To a suspension of Fmoc deprotected Sieber resin (0.62 mmol/g, 150 mg)in dry DMF was added 2-biphenyl carboxylic acid (77 mg) HOBt (29 mg),DIEA (138 μl) followed by TBTU (125 mg) and the suspension stirred atambient temperature for 2 hours. The resin was then washed (using DMF,methanol, DCM, methanol, DCM, methanol) then dried under vacuum.

EXAMPLES 3 to 8

Following the procedure described in Example 1, amides were preparedfrom the Sieber resin by treatment with benzo[b]thiophen-2-carbonylchloride (Example 3), 4-nitrobenzoyl chloride (Example 4),2,4-dimethoxybenzoyl chloride (Example 5), Fmoc-L-alanine (Example 6),Boc-L-alanine (Example 7) and 1,2,3,4-tetrahydronaphthoic acid (Example8).

EXAMPLE 9 3-Phenylpropionyl-Rink Resin

To a suspension of Fmoc deprotected Rink resin (0.59 mmol/g, 220 mg) indry DCM was added DIEA (112 μl) and 3-phenylpropionyl chloride (96μl)and the mixture stirred at ambient temperature for 1 hour. The resinwas then washed using DCM, methanol, DCM, methanol, then dried undervacuum.

EXAMPLE 10 Amide Derived From 4-Biphenylcarbonyl Chloride and Rink Resin

To a suspension of Fmoc deprotected Rink resin (0.59 mmol/g, 220 mg) indry DCM was added DIEA (112 μl) and 4-biphenylcarbonyl chloride (140 mg)and the mixture stirred at ambient temperature for 1 hour. The resin wasthen washed using DCM, methanol, DCM, methanol, then dried under vacuum.

EXAMPLE 11 3-Phenylpropionitrile

A solution of trifluoroacetic anhydride (43 μl) and dry pyridine (50 μl)in dry DCM (1.5 ml) was added to the resin prepared in example 1 (0.62mmol/g, 100 mg) and the suspension stirred under nitrogen at ambienttemperature overnight. The cleavage solution was filtered from the resinand evaporated to dryness. The residue was redissolved in ethyl acetate,washed with saturated NaHCO_(3(aq)), 1M KHSO₄, dried (MgSO₄) andevaporated to yield 3-phenylpropionitrile (8 mg, 98%).

ν_(max) 2249 cm⁻¹; δ_(H) 2.55 (2 H, t), 2.91 (2 H, t), 7.2 (5 H, m).

EXAMPLE 12 Benzo[b]thiophene-2-carbonitrile

The resin prepared in Example 3 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give benzo[b]thiophene-2-carbonitrile (5 mg,51%).

ν_(max) 2213 cm⁻¹; δ_(H) 7.45 (2 H, m), 7.83 (3 H, m).

EXAMPLE 13 4-Nitrobenzonitrile

The resin prepared in Example 4 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give 4-nitrobenzonitrile (9 mg, 98%)

ν_(max) 2232 cm⁻¹; δ_(H) 7.84 (2 H, d), 8.30 (2 H, d).

EXAMPLE 14 2,4-Dimethoxybenzonitrile

The resin prepared in Example 5 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give 2,4-dimethoxybenzonitrile (6 mg, 60%).

ν_(max) 2217 cm⁻¹; δ_(H) 3.79 (3 H, s), 3.84 (3 H, s), 6.4 (1 H, s),6.45 (1 H, d) 7.41 (1 H, d) m/z (ES+) 164 (M+H).

EXAMPLE 15 Biphenyl-2-carbonitrile

The resin prepared in Example 2 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give 2-biphenylcarbonitrile (9 mg, 82%).

ν_(max) 2222 cm⁻¹; δ_(H) 7.44 (7 H, m), 7.58 (1, H, t), 7.7 (1, H, d).

EXAMPLE 16 2-(Fmoc-amino)-2-methylacetonitrile

The resin prepared in Example 6 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give 2-(Fmoc-amino)-2-methylacetonitrile (9mg, 50%).

δ_(H) 1.49 (3 H, d), 4.16 (1 H, m), 4.43 (2 H, d), 4.62 (1 H, m), 4.99(1 H, m), 7.26 (2 H, t), 7.35 (2 H, t), 7.50 (2 H, d), 7.70 (2, H, d).m/z (ES+) 293 (M+H).

EXAMPLE 17 2-(Boc-amino)-2-methylacetonitrile

The resin prepared in Example 7 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give 2-(Boc-amino)-2-methylacetonitrile (9mg, 86%).

δ_(H) 1.41 (9 H, s), 1.49 (3 H, d), 4.55 (1 H, m), 4.75 (1 H, m); m/z(ES+) 171 (M+H).

EXAMPLE 18 1,2,3,4-Tetrahydro-2-naphthocarbonitrile

The resin prepared in Example 8 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 11 to give 1,2,3,4-tetrahydro-2-naphthocarbonitrile(9 mg, 93%).

ν_(max) 2237 cm⁻¹; δ_(H) 2.02 (1 H, m), 2.15 (1 H, m), 2.79 (1 H, m),2.89-3.11 (4 H, m) 6.95-7.16 (4 H, m).

EXAMPLE 19 Biphenyl-2-carbonitrile

The resin prepared in Example 2 (0.62 mmol/g, 100 mg) suspended in dryTHF was treated with (methoxycarbonylsulphamoyl)triethylammoniumhydroxide, inner salt (Burgess reagent) (44 mg) and the mixture refluxedunder nitrogen overnight. The cleavage solution was filtered from theresin and evaporated to dryness. The residue was redissolved in ethylacetate, washed with water, dried (MgSO₄) and evaporated to yieldbiphenyl-2-carbonitrile (2 mg, 18%).

ν_(max) 2222 cm⁻¹; δ_(H) 7.44 (7 H, m), 7.58 (1 H, t), 7.7 (1 H, d).

EXAMPLE 20 3-Phenylpropionitrile

The resin prepared in Example 1 (0.62 mmol/g 100 mg) was treated asdescribed in Example 19 to give 3-phenylpropionitrile (7 mg, 86%).

ν_(max) 2249 m⁻¹; δ_(H) 2.55 (2 H, t), 2.91 (2 H, t), 7.2 (5 H, m).

EXAMPLE 21 Biphenyl-2-carbonitrile

The resin prepared in Example 2 (0.62 mmol/g, 100 mg) suspended in dryDCM was treated with triethylamine (47 μl) and trichloroacetyl chloride(34 μl) and the mixture stirred at ambient temperature under nitrogenovernight. The cleavage solution was filtered from the resin andevaporated to dryness. The residue was redissolved in ethyl acetate,washed with saturated NaHCO₃(aq), 1M KHSO₄, dried (MgSO₄) andevaporated. The residue was chromatographed on silica gel using ethylacetate/hexane (1:9) for elution, yielding biphenyl-2-carbonitrile (7mg, 64%).

ν_(max) 2222 cm⁻¹; δ_(H) 7.44 (7 H, m), 7.58 (1 H, t), 7.7 (1 H, d).

EXAMPLE 22 3-Phenylpropionitrile

The resin prepared in Example 1 (0.62 mmol/g, 100 mg) was treated asdescribed in Example 20 to give 3-phenylpropionitrile (6 mg, 74%)

ν_(max) 2249 cm⁻¹; δ_(H) 2.55 (2 H, t), 2,91 (2 H, t), 7.2 (5 H, m).

EXAMPLE 23 3-Phenylpropionitrile

A solution of trifluoroacetic anhydride (83 μl) and dry pyridine (91 μl)in dry DCM (3 ml) was added to the resin prepared in Example 11 (0.59mmol/g,200 mg) and the suspension stirred under nitrogen at ambienttemperature overnight. The cleavage solution was filtered from the resinand evaporated to dryness. The residue was redissolved in ethyl acetate,washed with saturated NaHCO₃(aq), 1M KHSO₄, dried (MgSO₄) and evaporatedto yield 3-phenylpropionitrile (15 mg, 100%).

ν_(max) 2249 cm⁻¹; δ_(H) 2.55 (2 H, t), 2.91 (2 H, t), 7.2 (5 H, m).

EXAMPLE 24 4-Biphenylcarbonitrile

A solution of trifluoroacetic anhydride (83 μl) and dry pyridine (91 μl)in dry DCM (3 ml) was added to the resin prepared in Example 10 (0.59mmol/g, 200 mg) and the suspension stirred under nitrogen at ambienttemperature overnight. The cleavage solution was filtered from the resinand evaporated to dryness. The residue was redissolved in ethyl acetate,washed with saturated NaHCO₃(aq), 1M KHSO₄, dried (MgSO₄) and evaporatedto yield 4-biphenylcarbonitrile (22 mg, 100%).

δ_(H) 7.30-7.70 (9 H, m).

The reader's attention is directed to all papers and documents which arefiled concurrently with or previous to this specification in connectionwith this application and which are open to public inspection with thisspecification, and the contents of all such papers and documents areincorporated herein by reference.

All of the features disclosed in this specification (including anyaccompanying claims, abstract and drawings), and/or all of the steps ofany method or process so disclosed, may be combined in any combination,except combinations where at least some of such features and/or stepsare mutually exclusive.

Each feature disclosed in this specification (including any accompanyingclaims, abstract and drawings), may be replaced by alternative featuresserving the same, equivalent or similar purpose, unless expressly statedotherwise. Thus, unless expressly stated otherwise, each featuredisclosed is one example only of a generic series of equivalent orsimilar features.

The invention is not restricted to the details of the foregoingembodiment(s). The invention extend to any novel one, or any novelcombination, of the features disclosed in this specification (includingany accompanying claims, abstract and drawings), or to any novel one, orany novel combination, of the steps of any method or process sodisclosed.

What is claimed is:
 1. A method of preparing a nitrile compound, themethod comprising treating a solid supported amide to cause formation ofthe nitrile compound and cleavage from the support.
 2. A methodaccording to claim 1, wherein said amide is treated to dehydrate it. 3.A method according to claim 2, wherein cleavage and dehydration of theamide are accomplished in one operation.
 4. A method according to claim1, wherein said nitrile compound is of formula RCN where R represents anoptionally-substituted alicyclic, aliphatic or aromatic (which includesheteroaromatic) group.
 5. A method according to claim 4, wherein group Rincorporates an aromatic moiety and/or an amino group.
 6. A methodaccording to claim 1, wherein said amide is of formula RCONR²-SS whereinR² is a hydrogen atom or an optionally-substituted alkyl group and SSrepresents a solid support.
 7. A method according to claim 6, wherein SSincludes a moiety of formula

wherein the free bond is bonded to the nitrogen atom in the amide offormula II and wherein R³, R⁴ and R⁵, independently represent a hydrogenatom or an optionally-substituted alkyl or aromatic group, provided thatat least one of groups R³, R⁴, or R⁵ represents anoptionally-substituted aromatic group.
 8. A method according to claim 6,wherein R⁵ represents a hydrogen atom.
 9. A method according to claim 6,wherein R³ represents an optionally-substituted aromatic group.
 10. Amethod according to claim 7, wherein R⁴ represents anoptionally-substituted aromatic group.
 11. A method according to claim7, wherein one of R³ or R⁴ is linked to a polymer support.
 12. A methodaccording to claim 1, wherein formation of the nitrile compound andcleavage of it from the support occur substantially concurrently.
 13. Amethod according to claim 1, wherein, in the method, the amide isacetylated.
 14. A method according to claim 1, wherein said solidsupported amide is treated in the presence of a base.
 15. A methodaccording to claim 1, wherein said solid supported amide is treated inan aprotic solvent.
 16. A method according to claim 1, wherein saidsolid supported amide is treated at a temperature not exceeding 100° C.to prepare said nitrile compound.
 17. A method according to claim 1,wherein the nitrile compound is separated from the support byfiltration.
 18. A method of preparing a nitrile compound, the methodcomprising treating a solid supported amide to cause formation of thenitrile compound and cleavage from the support, wherein said amide is offormula RCONR²-SS, wherein R represents an optionally-substitutedalicyclic, aliphatic or aromatic group, R² is a hydrogen atom or anoptionally-substituted alkyl group and SS represents a solid support.19. A method of preparing a nitrile compound, the method comprisingtreating a solid supported amide to cause formation of the nitrilecompound and cleavage from the support, wherein formation of the nitrilecompound and cleavage of it from the support occur substantiallyconcurrently.
 20. An intermediate amide compound of formula RCONR²-SS,wherein R represents an optionally substituted alicyclic, aliphatic oraromatic group, R² is a hydrogen atom or an optionally-substituted alkylgroup and SS represents a solid support.